1. Field of the Invention
This invention relates to the preparation of fispemifene using ospemifene as a starting material.
2. Description of Related Art
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Ospemifene, (Z)-2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol, which is one of the main metabolites of toremifene, is known as an estrogen agonist and antagonist (Kangas, Cancer Chemother. Pharmacol. (1990) 27:8-12; WO 96/07402 and WO 97/32574). Ospemifene has relatively weak estrogenic and antiestrogenic effects in the classical hormonal tests (Kangas, 1990). It has anti-osteoporosis actions and it decreases total and LDL cholesterol levels in both experimental models and in human volunteers. It also has antitumor activity in an early stage of breast cancer development in an animal breast cancer model. Ospemifene is also the first SERM (selective estrogen receptor modulator) which has been shown to have beneficial effects in climacteric syndromes in healthy women. The use of ospemifene for the treatment of certain climacteric disorders and atrophy-related diseases or disorders in postmenopausal women is disclosed in WO 02/07718 and WO 03/103649.
WO 01/36360 describes a group of SERMs, which are tissue-specific estrogens and which can be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer's disease and/or cardiovascular diseases without the carcinogenic risk. Certain compounds can be given to men to protect them against osteoporosis, cardiovascular diseases and Alzheimer's disease without estrogenic adverse events (gynecomastia, decreased libido etc.). Of the compounds described in said patent publication, the compound (Z)-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol (also known under the generic name fispemifene) has shown a very interesting hormonal profile suggesting that it will be especially valuable for treating disorders in men. WO 2004/108645 and WO 2006/024689 suggest the use of fispemifene for treatment or prevention of age-related symptoms in men, such as lower urinary tract symptoms and diseases or disorders related to androgen deficiency in men.
Known methods for the syntheses of compounds like ospemifene and fispemifene include rather many steps. WO 02/090305 describes a method for the preparation of fispemifene, where, in a first step, a triphenylbutane compound with a dihydroxysubstituted butane chain is obtained. This compound is in a second step converted to a triphenylbutene where the chain is 4-chlorosubstituted. Then the desired Z-isomer is crystallized. Finally, the protecting group is removed to release the ethanol-ethoxy chain of the molecule.